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Bioavailability and
Bioequivalence
General concepts and overview
WHAT IS IT???
WHY IS IT???
HOW IS IT???
1. Chemistry 1. Chemistry
2. Manufacturing 2. Manufacturing
3. Controls 3. Controls
4. Labeling 4. Labeling
5. Testing 5. Testing
6. Animal Studies 6. Bioequivalence Study (In
7. Clinical Studies Vivo, In vitro)
(Bioavailability) •
drug applications are termed " abbreviated " because they are generally
d to include preclinical ( animal ) and clinical ( human ) data to establish safety and effectiveness
ric applicants must scientifically demonstrate that their product is bioequivalent
s in the same manner as the origina; drug).
FDA Definitions Used in
Bioequivalence Determinations
FDA Determinations of Bioequivalence
Main Terms
• Pharmaceutical equivalents
• Pharmaceutical alternatives
• Therapeutic equivalents
• Bioavailability
• Bioequivalence
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site.
Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms.
Accessed September 29, 2003.
Pharmaceutical Equivalents
• Drug products are considered
pharmaceutical equivalents if they
contain the same active ingredient(s),
have the same dosage form and route of
administration, and are identical in
strength or concentration
• Equivalent products contain the same
amount of ingredient in the same dosage
form but may differ in characteristics,
such
Approved as shape,
Drug Products With Therapeutic release mechanisms,
Equivalence Evaluations . 23 ed. 2003. FDAand
rd /CDER
packaging
Web site . Available
September 29, 2003.
at : http ://www .fda . gov /cder/ob /docs /preface /ecpreface .htm . Accessed
Pharmaceutical Alternatives
0.0
0 25
Time ( h )
Why do we care about BIOAVAILABILITY?
The “true dose” is not the drug swallowed;
BUT is the drug available to exert its effect.
•� Dissolution
•� Absorption
•� Survive metabolism
May have a drug with very low bioavailability
•� Dosage form or drug may not dissolve readily
•� Drug may not be readily pass across biological
membranes (i.e. be absorbed)
•� Drug may be extensively metabolized during
absorption process (first-pass, gut wall, liver)
Important component of overall variability
•� Variable bioavailability may produce variable exposure
Rate versus Extent of Absorption
Extent of absorption is reflected by AUC
Rate of absorption, ka, is reflected by Tmax
Both Rate and Extent of absorption affect Cmax
2.Pharmaceutical ingredients
3.Special coatings
1.Parentral administration
2.Oral administration
3.Rectal administration
4.Topical administration
Bioequivalence
• A comparison of the bioavailability of two or
more
• drug products.
• Two products or formulations containing the
same
• active ingredient are bioequivalent if their
rates
• and extents of absorption are the same
Bioequivalence
• Approved may be
Drug Products With Therapeutic demonstrated
Equivalence Evaluations. 23 ed. 2003. FDA/CDER Web
rd
site. through in://www
Available at: http vivo or
.fda.gov /cderin vitro
/ob/docs test
/preface methods,
/ecpreface .htm#Therapeutic
Equivalence-Related Terms. Accessed September 29, 2003.
comparative clinical trials, or
Bioequivalence
90
Concentration (ng/mL)
80
70
60
Test/Generic
50
Reference/Brand
40
30
20
10
0
0 5 10 15 20 25 30
Time (hours)
Regulatory Bioequivalence: An
Overview
“Self-evident” - Biowaivers granted
Solutions Condition- excipients do not alter absorption
(historical data)
Suspensions
Pre-1962 DESI Drugs: In Vivo
SUPAC-IR (1995)
Chewable, etc. evaluation for “bio-problem”
Dissolution-IR
drugs (TI, PK, P-Chem)
BCS
Conventional Post-1962 Drugs: Generally
(pre-/post approval)
Tablets In Vivo - some exceptions
Capsules (IVIVC..)
MR Products
SUPAC-MR
In VIVO
IVIVC
Bioequivalence: IR
Products
Pharmaceutical Equivalent
Products
Reference Test
Possible Differences
Drug particle size, ..
Excipients
N o rm a lh e a lth y
Manufacturing process
su b je cts
Equipment C ro sso ve r d e sig n
Site of manufacture O ve rn ig h t fa st
G la ss o f w a te r
Batch size …. 9 0 % C I w ith in 8 0 -
125%
Documented Bioequivalence
o f R e f. ( C m a x & A U C )
= Therapeutic Equivalence
(Note: Generally, same dissolution
Ajaz Hussain, FDA spec.)
FDA Methods to Determine
Bioequivalence
• Generic drug manufacturers must
demonstrate that a drug is
bioequivalent to a reference drug
product
• In order of FDA preference, methods
used to define bioequivalence
– Pharmacokinetic studies
– Pharmacodynamic studies
– Comparative clinical trials
– In vitro
Food and Drug Administration studies
. Code of Federal Regulations. Title 21, Part 320: Bioavailability
and Bioequivalence Requirements. Section 320.24. 2003. Available at: http://www.accessdata.fda.gov.
Pharmacokinetic Studies
Key Measurements
S tu d y C o m p o u n d • AUC
R e fe re n ce – Area under the
C oC mma p o u n d concentration- time curve
• Cmax
x
– Maximum concentration
C o n ce n tra tio
– Time to maximum
concentration
Tmax Tim
Approved Drug Products With Therapeutic e
Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at:
http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.
Comparative
Pharmacodynamic Studies
• Not recommended when:
– active ingredient is absorbed into the
systemic circulation
– pharmacokinetic study can be
conducted
• Local action / no systemic absorption
• eg. : Topical Corticosteroid
29 Hanoi, 2006-19-01
Comparative Clinical
Studies
• Pharmacokinetic profile not possible
• Lack of suitable pharmacodynamic
endpoint
•
• eg . : (Nasal suspensions)
30 Hanoi, 2006-19-01
Study Designs
33 Hanoi, 2006-19-01
Disadv. of cross over
design
• The main problem with the cross
over design is :
The carry over effect………!?
Fasted vs. Fed Designs
•
• Fasted study design preferred
– Minimize variability not attributable to
formulation
– Better able to detect formulation
differences
35 Hanoi, 2006-19-01
Fed Study Designs may be
employed when:
• Significant gastrointestinal (GI)
disturbance caused by fasted
administration
• Product labeling restricts
administration to fed state
36 Hanoi, 2006-19-01
When equivalence studies are
NOT necessary (Biowaivers)
• A-
• Aqueous parenteral solutions
• Solutions for oral use ( syrups, elixirs,
tinctures & other soluble forms but not
suspensions)
• Pdrs for reconstitution as a solution
• Otic or ophthalmic aqueous solutions
• Topical aqueous solutions
• Aqueous nebulizing inhalations or nasal
sprays
• B. For some products bioequivalence
may be demonstrated by evidence
obtained in vitro instead of in vivo
data:
– The drug product is in the same dosage
form, but in a different strength, and is
proportionally similar in its active and
inactive ingredients to another product
by the same manufacturer that was
found to be bioequivalent.
•
• For high potency drug substances,
the same inactive ingredients are
used for all strengths, and the
change in any strength is obtained
by altering the amount of the
active ingredients and one or more
of the inactive ingerdientsare within
the limits defined by the SUPAC
guidances (up to level II).
Waiver of Bioavailability
and Bioequivalence Studies
for Immediate-Release
Solid Oral Dosage Forms
Based on a
Biopharmaceutics
Classification System
(B.C.S)
BCS Classifications
According to the BCS, drug
substances are classified as follows:
•
n A drug product is considered to be
RAPIDLY DISSOLVING when > 85% of
the labeled amount of drug substance
dissolves within 30 minutes using USP
apparatus I or II in a volume of < 900 ml
buffer solutions.
BCS Class I: Dissolution
n USP Apparatus I (100 rpm) or II (50 rpm)
n Three media
Ø 0.1 N HCl or SGF USP without enzymes 0.1
N HCl or SGF USP without enzymes
Ø pH 4.5 buffer pH 4.5 buffer
Ø pH 6.8 buffer or SIF USP without enzymes
n NLT 85% dissolves within 30 minutes
n Similarity factor (f2) for test (T) v. reference
(R) profile comparisons should > 50
Thank you